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Tolvaptan, a selective vasopressin receptor antagonist, is a Class IV agent of Biopharmaceutical Classification System (BCS). To improve bioavailability after oral administration, the new tolvaptan-loaded self-microemulsifying drug delivery system (SMEDDS) was further optimized using a “design of the experiment (DoE)” including components of D-optional mixture design. Based on a solubility study of tolvaptan in various oils, surfactants, and cosurfactants, Capryol® 90, Tween 20, and Transcutol® HP [or polyethylene glycol 200 (PEG 200)] were finally selected for optimization of tolvaptan-loaded SMEDDS formulations. The fitting models of, and poly-nominal equations for, all response variables were acceptable, as revealed by analysis of variance (ANOVA, R2 > 0.900, p < 0.0001). The optimized formulations A-1 (Capryol® 90/Tween 20/Transcutol® HP = 10%/70%/20% w/w) and B-1 (Capryol® 90/Tween 20/PEG 200 = 10%/70%/20% w/w) with desirabilities of 0.905 and 1.000, respectively, showed low droplet size and the dissolution rate exceeded 95% at 15 and 60 min. The tolvaptan-loaded SMEDDS remained stable for 3 months under accelerated conditions, thus with no change in any of content, color, particle size, or dissolution rate. In a rat pharmacokinetic study, the bioavailability of formulations A-1 (16.6%) and B-1 (11.5%) were 23–33-fold higher than that of raw tolvaptan powder (0.5%). Thus, the use of “quality by design (QbD)” during development of tolvaptan-loaded SMEDDS improved the dissolution rate and oral drug bioavailability.

Yttria-stabilized zirconia (YSZ), a thermal barrier coating material characterized by low thermal conductivity, is typically deposited via electron beam-physical vapor deposition. Notably, oxygen depletion occurs during this process, causing color changes in YSZ. Therefore, YSZ is speculated to undergo phase transformation during this process, which demands careful consideration owing to its effect on the life of thermal coatings. To study this phenomenon, bulk samples were prepared, subjected to vacuum heat treatment to induce oxygen depletion, and followed by oxidative heat treatment. Experimental results showed that the color of the samples changed to black after the vacuum heat treatment and to a lighter color after the oxidative heat treatment. In addition, X-ray diffraction and Raman analyses were performed. The monoclinic phase formation was confirmed during the vacuum heat treatment; however, it disappeared after the oxidation heat treatment. The coating obtained in a high vacuum atmosphere exhibited a black color and cubic phase, which changed to a bright color and tetragonal phase after the oxidation heat treatment.

The purpose of the present investigation was to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) for improving the oral absorption of a pranlukast hemihydrate (PLH), a very poorly water-soluble drug. An efficient self-microemulsifying vehicle for PLH was selected and optimized using solubility testing and phase diagram construction. The formulations were characterized by assessing self-emulsification performance, droplet size analysis, in vitro drug release characteristics and formulation stability studies. Optimized formulations for in vitro dissolution and bioavailability assessment were Triethylcitrate (TEC; 10%), Tween 20 (50%), Span 20 (25%), triethanolamine (5%), and benzyl alcohol (10%). The SMEDDS readily released the lipid phase to form a fine oil-in-water microemulsion with a narrow distribution size. Saturated solubilities of PLH from SMEDDS in water, pH 4.0 and 6.8, were over 150 times greater than that of plain PLH. The release of 100% PLH from SMEDDS was considerably greater compared to only 1.12% in simulated intestinal fluid (pH 6.8) from plain PLH after 2 hours. The PLH suspension with 0.5% sodium carboxymethylcellulose or 3% PLH-loaded SMEDDS was administrated at a dose of 40 mg/kg as PLH to fasted rats. The absorption of PLH from SMEDDS resulted in about a threefold increase in bioavailability compared with plain PLH aqueous suspension. Our studies illustrated that the potential use of the new SMEDDS can be used as a possible alternative to oral delivery of a poorly water-soluble drug such as PLH.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by cognitive deficits, which are accompanied by memory loss and cognitive disruption. Rhodiola sachalinensis (RSE) is a medicinal plant that has been used in northeastern Asia for various pharmacological activities. We attempted to carry out the bioconversion of RSE (Bio-RSE) using the mycelium of Bovista plumbe to obtain tyrosol-enriched Bio-RSE. The objective of this study was to investigate the effects of Bio-RSE on the activation of the cholinergic system and the inhibition of oxidative stress in mice with scopolamine (Sco)-induced memory impairment. Sco (1 mg/kg body weight, i.p.) impaired the mice’s performance on the Y-maze test, passive avoidance test, and water maze test. However, the number of abnormal behaviors was reduced in the groups supplemented with Bio-RSE. Bio-RSE treatment improved working memory and avoidance times against electronic shock, increased step-through latency, and reduced the time to reach the escape zone in the water maze test. Bio-RSE dramatically improved the cholinergic system by decreasing acetylcholinesterase activity and regulated oxidative stress by increasing antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)). The reduction in nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling in the brain tissue due to scopolamine was restored by the administration of Bio-RSE. Bio-RSE also significantly decreased amyloid-beta 1–42 (Aβ1–42) and amyloid precursor protein (APP) expression. Moreover, the increased malondialdehyde (MDA) level and low total antioxidant capacity in Sco-treated mouse brains were reversed by Bio-RSE, and an increase in Nrf2 and HO-1 was also observed. In conclusion, Bio-RSE protected against Sco-induced cognitive impairment by activating Nrf2/HO-1 signaling and may be developed as a potential beneficial material for AD.

Rivaroxaban (RXB), a novel oral anticoagulant that directly inhibits factor Xa, is a poorly soluble drug belonging to Biopharmaceutics Classification System (BCS) class II. In this study, a hot-melt extruded amorphous solid dispersion (HME-ASD) containing RXB is prepared by changing the drug:polymer ratio (Polyvinylpyrrolidione-vinyl acetate 64, 1:1–1:4) and barrel temperature (200–240 °C), fixed at 20% of Cremophor® RH 40 and 15 rpm of the screw speed, using the hot-melt extruding technique. This study evaluates the solubility, dissolution behavior, and bioavailability for application to oral drug delivery and optimizes the formulation of rivaroxaban amorphous solid dispersion (RXB-ASD). Based on a central composite design, optimized RXB-ASD (PVP VA 64 ratio 1:4.1, barrel temperature 216.1 °C, Cremophor® RH 40 20%, screw speed 15 rpm) showed satisfactory results for dependent variables. An in vitro drug dissolution study exhibited relatively high dissolution in four media and achieved around an 80% cumulative drug release in 120 min. Optimized RXB-ASD was stable under the accelerated condition for three months without a change in crystallinity and the dissolution rate. A pharmacokinetic study of RXB-ASD in rats showed that the absorption was markedly increased in terms of rate and amount, i.e., the systemic exposure values, compared to raw RXB powder. These results showed the application of quality by design (QbD) in the formulation development of hot-melt extruded RXB-ASD, which can be used as an oral drug delivery system by increasing the dissolution rate and bioavailability.

Raloxifene hydrochloride (RLH) was formulated into a pH-modified supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) to increase drug solubility and dissolution rate. Optimal formulations of pH-modified S-SMEDDSs were developed by incorporating hydroxypropyl-cellulose-L as a precipitation inhibitor and phosphoric acid as a pH modifier (an acidifier). RLH was dissolved to greater extents by all pH-modified S-SMEDDSs compared with non-pH-modified S-SMEDDSs. In particular, phosphoric acid afforded greater drug dissolution than did the other acidifiers tested, perhaps because phosphoric acid better controlled the pH. More than 50% of the RLH was released from the pH-modified S-SMEDDS at pH 2.5 compared with only ~5% of the drug into aqueous buffer (pH 1.2 or 6.8) after dissolution of a conventional tablet. pH-modified S-SMEDDSs with a hydrophilic polymer and phosphoric acid improved the dissolution behavior of a drug exhibiting poor aqueous solubility.

External quality assessment (EQA) is essential for ensuring reliable test results, especially when laboratories are using assays authorized for emergency use for newly emerging pathogens. We developed an EQA panel to assess the quality of real-time reverse transcription PCR assays being used in South Korea to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the participation of 23 public health organization laboratories and 95 nongovernmental laboratories involved in SARS-CoV-2 testing, we conducted qualitative and semiquantitative performance assessments by using pooled respiratory samples containing different viral loads of SARS-CoV-2 or human coronavirus OC43. A total of 110 (93.2%) laboratories reported correct results for all qualitative tests; 29 (24.6%) laboratories had >1 outliers according to cycle threshold values. Our EQA panel identified the potential weaknesses of currently available commercial reagent kits. The methodology we used can provide practical experience for those planning to conduct evaluations for testing of SARS-CoV-2 and other emerging pathogens in the future.

Background Information on electrocardiogram (ECG) has not been quantified in obstructive coronary artery disease (ObCAD), despite the deep learning (DL) algorithm being proposed as an effective diagnostic tool for acute myocardial infarction (AMI). Therefore, this study adopted a DL algorithm to suggest the screening of ObCAD from ECG. Methods ECG voltage-time traces within a week from coronary angiography (CAG) were extracted for the patients who received CAG for suspected CAD in a single tertiary hospital from 2008 to 2020. After separating the AMI group, those were classified into ObCAD and non-ObCAD groups based on the CAG results. A DL-based model adopting ResNet was built to extract information from ECG data in the patients with ObCAD relative to those with non-ObCAD, and compared the performance with AMI. Moreover, subgroup analysis was conducted using ECG patterns of computer-assisted ECG interpretation. Results The DL model demonstrated modest performance in suggesting the probability of ObCAD but excellent performance in detecting AMI. The AUC of the ObCAD model adopting 1D ResNet was 0.693 and 0.923 in detecting AMI. The accuracy, sensitivity, specificity, and F1 score of the DL model for screening ObCAD were 0.638, 0.639, 0.636, and 0.634, respectively, while the figures were up to 0.885, 0.769, 0.921, and 0.758 for detecting AMI, respectively. Subgroup analysis showed that the difference between normal and abnormal/borderline ECG groups was not notable. Conclusions ECG-based DL model showed fair performance for assessing ObCAD and it may serve as an adjunct to the pre-test probability in patients with suspected ObCAD during the initial evaluation. With further refinement and evaluation, ECG coupled with the DL algorithm may provide potential front-line screening support in the resource-intensive diagnostic pathways.

The purpose of this study is to identify the crack initiation and damage stress thresholds of granite from the Korea atomic energy research institute’s Underground Research Tunnel (KURT). From this, a quantitative damage evolution was inferred using various methods, including the crack volumetric strain, b value, the damage parameter from the moment tensor, and the acoustic emission (AE) energy. Uniaxial compression tests were conducted, during which both the stress–strain and AE activity were recorded simultaneously. The crack initiation threshold was found at a stress level of 0.42–0.53  σ c , and the crack damage threshold was identified at 0.62–0.84  σ c . The normalized integrity of KURT granite was inferred at each stress level from the damage parameter by assuming that the damage is accumulated beyond the crack initiation stress threshold. The maximum deviation between the crack volumetric strain and the AE method was 16.0 %, which was noted at a stress level of 0.84  σ c . The damage parameters of KURT granite derived from a mechanically measured stress–strain relationship (crack volumetric strain) were successfully related and compared to those derived from physically detected acoustic emission waves. From a comprehensive comparison of damage identification and quantification methods, it was finally suggested that damage estimations using the AE energy method are preferred from the perspectives of practical field applicability and the reliability of the obtained damage values.

The prostaglandin D2 receptor 1 (DP1), a member of the prostanoid G protein-coupled receptor (GPCR) family, plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, we present five high-resolution cryo-electron microscopy (cryo-EM) structures of the human DP1 receptor, including an apo structure, two inactive state structures bound to two different inverse agonists developed by ONO Pharmaceutical, and two active state structures in complex with the G s protein and bound to the endogenous agonist PGD2 and its selective derivative BW245C. Structural analysis, complemented by molecular dynamics simulations and site-directed mutagenesis, reveals key residues involved in ligand recognition and suggests a distinct activation mechanism for DP1, which lacks most of the conserved class A GPCR motifs. Notably, the unique residue K76 within the conserved sodium pocket acts as a major activation switch, while amphiphilic helix 8 adopts an unconventional orientation essential for receptor function. These findings offer valuable insights into the structure and function of prostanoid receptors and may facilitate the development of therapeutics targeting DP1. The prostaglandin DP1 receptor plays critical roles in allergic responses, sleep regulation, immune modulation, and vasodilation. Here, authors present atomic structures of DP1 in different states revealing molecular mechanisms of receptor inhibition and activation.